scholarly journals Genomic Adaption and Mutational Patterns in a HaCaT Subline Resistant to Alkylating Agents and Ionizing Radiation

2021 ◽  
Vol 22 (3) ◽  
pp. 1146
Author(s):  
Reinhard Ullmann ◽  
Benjamin Valentin Becker ◽  
Simone Rothmiller ◽  
Annette Schmidt ◽  
Horst Thiermann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Line ◽  
Copy Number ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Chromosomal Translocations ◽  
Dna Copy Number ◽  
Mutational Signatures ◽  
Copy Number Changes ◽  
And Oxidative Stress

Sulfur mustard (SM) is a chemical warfare agent that can damage DNA via alkylation and oxidative stress. Because of its genotoxicity, SM is cancerogenic and the progenitor of many chemotherapeutics. Previously, we developed an SM-resistant cell line via chronic exposure of the popular keratinocyte cell line HaCaT to increasing doses of SM over a period of 40 months. In this study, we compared the genomic landscape of the SM-resistant cell line HaCaT/SM to its sensitive parental line HaCaT in order to gain insights into genetic changes associated with continuous alkylation and oxidative stress. We established chromosome numbers by cytogenetics, analyzed DNA copy number changes by means of array Comparative Genomic Hybridization (array CGH), employed the genome-wide chromosome conformation capture technique Hi-C to detect chromosomal translocations, and derived mutational signatures by whole-genome sequencing. We observed that chronic SM exposure eliminated the initially prevailing hypotetraploid cell population in favor of a hyperdiploid one, which contrasts with previous observations that link polyploidization to increased tolerance and adaptability toward genotoxic stress. Furthermore, we observed an accumulation of chromosomal translocations, frequently flanked by DNA copy number changes, which indicates a high rate of DNA double-strand breaks and their misrepair. HaCaT/SM-specific single-nucleotide variants showed enrichment of C > A and T > A transversions and a lower rate of deaminated cytosines in the CpG dinucleotide context. Given the frequent use of HaCaT in toxicology, this study provides a valuable data source with respect to the original genotype of HaCaT and the mutational signatures associated with chronic alkylation and oxidative stress.

Mitochondrial DNA Copy Number in Peripheral Blood in the First Trimester of Pregnancy and Different Preeclampsia Clinical Phenotypes Development: A Pilot Study

2018 ◽  
Vol 26 (8) ◽  
pp. 1054-1061 ◽  
Author(s):  
Andrea Busnelli ◽  
Debora Lattuada ◽  
Stefania Ferrari ◽  
Marco Reschini ◽  
Barbara Colciaghi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dna ◽  
Peripheral Blood ◽  
Copy Number ◽  
First Trimester ◽  
Control Group ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
First Trimester Of Pregnancy ◽  
And Oxidative Stress

Inflammation and oxidative stress are intrinsically linked to early poor placentation, typical of pregnancies complicated by preeclampsia associated with intrauterine growth restriction (PE-IUGR). Low mitochondrial DNA copy number (mtDNAcn) in peripheral blood constitutes a good peripheral surrogate marker of inflammation and oxidative stress. On these basis, we explored a possible correlation between mtDNAcn in peripheral blood in the first trimester of pregnancy and the PE-IUGR onset. To shed light on this issue, we setup a nested case–control study from a prospective cohort of pregnant women undergoing first-trimester aneuploidies screening. Two groups of patients affected by PE classified according to the clinical phenotype were identified: (1) patients who developed PE-IUGR and (2) patients who developed PE associated with appropriate for gestational age intrauterine fetal growth (PE-AGAf). Controls were women with a physiologic pregnancy matched to cases on the basis of age (±6 months, ratio 2:1). Mitochondrial DNA copy number was quantified using real-time polymerase chain reaction and normalized to nuclear DNA. The median (interquartile range) mtDNAcn in peripheral blood in patients with PE-IUGR (n = 12) and in patients with PE-AGAf (n = 16) was 70 (44-97) and 108 (95-145), respectively ( P = .004). Both these values were significantly lower than that detected in the control group (161[133-183], P < .001). The area under the receiver–operator curve for PE-IUGR and PE-AGAf were 0.94 (95% confidence interval [CI]: 0.88-1.00, P < .001) and 0.81 (95%CI: 0.70-0.91, P < .001), respectively. In conclusion, MtDNAcn in peripheral blood resulted significantly lower both in patients affected by PE-IUGR and in those affected by PE-AGAf when compared to controls. The accuracy of this biomarker resulted particularly good in predicting PE-IUGR.

Platinum pyridinecarboxaldimine complexes containing boronate esters

2004 ◽  
Vol 82 (12) ◽  
pp. 1692-1699 ◽  
Author(s):  
Hanni A Darwish ◽  
Stephen J Scales ◽  
Jennifer L Horton ◽  
Liliya G Nikolcheva ◽  
Haiwen Zhang ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Key Words ◽  
Cell Line ◽  
Platinum Complexes ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Boronate Esters ◽  
Human Ovarian Carcinoma

Condensation of 2-pyridinecarboxaldehydes with 2-, 3-, and 4-H2NC6H4Bpin (pin = 1,2-O2C2Me4) gave the corresponding boron-containing pyridinecarboxaldimines (N–NBpin). Addition of these ligands to [PtCl2(coe)]2 (coe = cis-cyclooctene) gave complexes of the type cis-PtCl2(N–NBpin) in moderate yields. The platinum complexes have been examined for their potential cytotoxicities against OV2008 (human ovarian carcinoma) and the analogous cisplatin-resistant cell line C13. Key words: boronate esters, pyridinecarboxaldimines, cytotoxicity, platinum, boron.

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